U.S. patent application number 11/166862 was filed with the patent office on 2005-10-27 for melanoma therapy.
Invention is credited to Rose, Esther Helen, Rybak, Mary Ellen.
Application Number | 20050238621 11/166862 |
Document ID | / |
Family ID | 26826471 |
Filed Date | 2005-10-27 |
United States Patent
Application |
20050238621 |
Kind Code |
A1 |
Rybak, Mary Ellen ; et
al. |
October 27, 2005 |
Melanoma therapy
Abstract
Methods for treating treatment-naive as well as
treatment-experienced patients having melanoma to increase the
progression-free survival time involving administering a
therapeutically effective amount of pegylated interferon-alpha,
e.g., preferably pegylated interferon alpha-2b, as adjuvant therapy
to definitive surgery are disclosed.
Inventors: |
Rybak, Mary Ellen; (Warren,
NJ) ; Rose, Esther Helen; (Westfield, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION
PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Family ID: |
26826471 |
Appl. No.: |
11/166862 |
Filed: |
June 24, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11166862 |
Jun 24, 2005 |
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09904263 |
Jul 12, 2001 |
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6923966 |
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09904263 |
Jul 12, 2001 |
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09545312 |
Apr 7, 2000 |
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60128308 |
Apr 8, 1999 |
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Current U.S.
Class: |
424/85.7 |
Current CPC
Class: |
A61K 38/212
20130101 |
Class at
Publication: |
424/085.7 |
International
Class: |
A61K 038/21 |
Claims
What is claimed is:
1. A method of treating a patient having melanoma which has been
surgically removed, which comprises administering to such a patient
a therapeutically effective dose of pegylated interferon alpha for
a time period sufficient to increase progression-free survival
time.
2. The method of claim 1 wherein the pegylated interferon is
pegylated interferon alpha-2a or pegylated interferon alpha-2b.
3. The method of claim 2 wherein the patient is a treatment-naive
patient.
4. The method of claim 3 wherein the treatment-naive patient is one
having newly diagnosed melanoma.
5. The method of claim 1 wherein the patient is
treatment-experienced patient.
6. The method of claim 5 wherein the treatment experienced patient
is intolerant to interferon alpha or resistant to interferon
alpha.
7. The method of claim 1 wherein the time period is at least about
24 months.
8. The method of claim 1 wherein the pegylated interferon alpha
administered after surgical excision of the primary melanoma.
9. The method of claim 1 wherein the pegylated interferon alpha is
pegylated interferon alpha-2b and the effective amount is in the
range of about 3.0 micrograms/kg to 9.0 micrograms/kg administered
once a week.
10. The method of claim 1 wherein the pegylated interferon alpha is
pegylated alpha-2a and the effective amount is in the range of
about 200 microgram to 250 administered once a week.
11. A method of treating a patient having cutaneous melanoma which
has been surgically removed which comprises administering to said
patient an effective amount of pegylated interferon-alpha once a
week for a time period sufficient to increase progression-free
survival time.
12. The method of claim 11 wherein the pegylated interferon alpha
is pegylated interferon alpha-2b and the effective amount is in the
range of about 3.0 micrograms/kg to 9.0 micrograms/kg administered
once a week.
13. The method of claim 11 wherein the pegylated interferon alpha
is pegylated alpha-2a and the effective amount is in the range of
about 200 microgram to 250 administered once a week.
14. The method of claim 11 wherein the time period is at least
about 100 weeks.
15. A method of treating a patient having cutaneous melanoma which
comprises administering to such a patient about 3.0 micro-grams/kg
to about 9.0 micrograms/kg of pegylated interferon alpha-2b once a
week for a time period sufficient to increase the progression-free
survival time.
16. The method of claim 15 wherein the time period is about 100
weeks.
17. The method of claim 15 wherein about 4.5 to about 6.5
micrograms/kg of pegylated interferon alpha-2b is administered once
a week.
18. A method comprising the step of marketing a therapeutically
effective dose of pegylated interferon alpha for administration to
a patient with melanoma within about 60 days of surgery in a
protocol extending for a time period of at least about 100
weeks.
19. The method of claim 18 wherein the pegylated interferon alpha
is pegylated interferon alpha-2b and the effective amount is in the
range of about 3.0 micrograms/kg to 9.0 micrograms/kg administered
once a week.
20. The method of claim 18 wherein the pegylated interferon alpha
is pegylated alpha-2a and the effective amount is in the range of
about 200 microgram to 250 administered once a week.
Description
[0001] This application claims the benefit of U.S. provisional
patent application Ser. No. 60/128,308 filed Apr. 8, 1999.
[0002] Throughout this disclosure, various publications, patents
and patent applications are referenced. The disclosures of these
publications, patents and patent applications are herein
incorporated by reference.
BACKGROUND OF THE INVENTION
[0003] This invention relates to an improved therapy for treating
patients having melanoma after definitive surgical removal of the
lesions by administering a therapeutically effective dose of
pegylated interferon-alpha for a time sufficient to increase
progression-free survival time.
[0004] Melanoma incidence is increasing at a rate that exceeds all
that for other solid tumors. Patients with primary melanoma of
greater than 4 mm or metastatic melanoma involving regional lymph
nodes possess a 50 to 90% mortality risk following surgical
excision of the primary melanomas.
[0005] Recently, the Eastern Cooperative Oncology Group ("ECOG")
published results of the use of interferon alpha-2b in patients
with stage III cutaneous melanoma as adjuvant therapy following
surgery for deep primary (T4) or regionally metastatic (N1)
melanoma (Kirkwood, J. M., et al. J. Clin. Oncol., Vol 14: (1996)
pages 4-17.) The interferon alpha-2b therapy used by ECOG involved
an induction phase of 20 million IU of interferon alpha-2b per
square meter of body surface area (m.sup.2) administered
intravenously ("IV") daily for five days every week for four weeks
followed by maintenance interferon alpha therapy of 10 million
IU/M.sup.2 administered subcutaneously ("SC") three times a week
("TIW") for 48 weeks. A significant improvement in median
disease-free survival and overall survival were observed versus
control (observation) despite dosage reductions or delays for
toxicity in 50% of the patients during the IV induction therapy
phase and in 48% of the patients in the SC maintenance phase.
Hematologic, neurologic and constitutional toxicities occurred
among these patients requiring dose reduction or withdrawal from
the interferon alpha therapy. Subject compliance with the dosage
and dosage regimen during both phases is considered to be important
to achieve maximum clinical benefit. Accordingly, there is a need
for improved therapy for treating patients having melanoma with
higher patient compliance.
SUMMARY OF THE INVENTION
[0006] The present invention provides a method of treating a
patient having melanoma which has been surgically removed, which
comprises administering to such a patient a therapeutically
effective dose of pegylated interferon alpha for a time period
sufficient to increase the progression-free survival time.
[0007] The present invention also provides a method of treating a
patient having cutaneous melanoma which has been surgically
removed, which comprises administering to said patient an effective
amount of pegylated interferon-alpha once a week for a time period
sufficient to increase progression-free survival time.
[0008] The present invention further provides a method of treating
a patient having cutaneous melanoma which has been surgically
removed which comprises administering to such a patient about 3.0
micrograms/kg to about 9.0 micrograms/kg of pegylated interferon
alpha-2b once a week for a time period sufficient to increase
progression-free survival time. In preferred embodiments, 6.0
micrograms per kilogram is dosed weekly to a patient for eight
weeks, and 3.0 micrograms per kilogram or less weekly is dosed to
the patient for a period of five years minus the eight weeks of
initial dosage. If less than 3.0 micrograms per kilogram are dosed
to the patient, preferably the dose reduction steps are 3.0-2.0-1.0
micrograms per kilogram.
[0009] The present invention further provides a method comprising
the step of marketing a therapeutically effective dose of
interferon alpha for administration to a patient with melanoma
within about 60 days of surgery in a protocol extending for a time
period of at least about 100 weeks.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The present invention provides an improved method of
treating patients with melanoma especially those in State IIB
(lesions>4 mm, but without positive nodes)and Stage III
(lesions>4 mm and node-positive) primary cutaneous melanoma,
preferably after surgery for their State IIB or Stage III melanoma.
The improved method provides a safer and more efficacious and
tolerable adjuvant therapy treatment for melanoma by use of weekly
injections of pegylated interferon. The melanoma patients treatable
in accordance with the improved method of the present invention
include those newly diagnosed with this disease who were free of
disease 56 days post surgery but at high risk for systemic
recurrence of the disease. The term "high risk patients" as used
herein means those melanoma patients with lesions of Breslow
thickness >4 mm as well as those patients with lesions of any
Breslow thickness with primary or recurrent nodal involvement.
Melanoma patients intolerant or resistant to interferon alpha
therapy are also included. Treatment with pegylated interferon
alpha in accordance with the present invention will continue for a
minimum of about two years (about 100-104 weeks) and up to five
years, unless there is clinical evidence of disease progression,
unacceptable toxicity or the patient requests that the therapy be
discontinued.
[0011] When the pegylated interferon-alpha administered is a
pegylated interferon alpha-2b, the therapeutically effective amount
of pegylated interferon alpha-2b administered is in the range of
about 3.0 to about 9.0 micrograms per kilogram of pegylated
interferon alpha-2b administered once a week (QW), preferably in
the range of about 4.5 to about 6.5 micrograms per kilogram of
pegylated interferon alpha-2b QW, more preferably in the range of
about 5.5 to about 6.5 micrograms per kilogram of pegylated
interferon alpha-2b QW, and most preferably in the range of about
6.0 micrograms per kilogram of pegylated interferon alpha-2b
administered QW.
[0012] In preferred embodiments, 6.0 micrograms per kilogram is
dosed weekly to a patient for eight weeks, and 3.0 micrograms per
kilogram or less weekly is dosed to the patient for a period of
five years minus the eight weeks of initial dosage. If less than
3.0 micrograms per kilogram are dosed to the patient, preferably
the dose reduction steps are 3.0-2.0-1.0 micrograms per
kilogram.
[0013] When the pegylated interferon-alpha administered is a
pegylated interferon alpha-2a, the therapeutically effective amount
of pegylated interferon alpha-2a administered is in the range of
about 50 micrograms to about 500 micrograms once a week("QW"),
preferably about 200 micrograms to about 250 micrograms QW.
[0014] The term "pegylated interferon alpha" as used herein means
polyethylene glycol modified conjugates of interferon alpha,
preferably interferon alpha-2a and -2b. The preferred
polyethylene-glycol-interferon alpha-2b conjugate is
PEG.sub.12000-interferon alpha 2b. The phrases "12,000 molecular
weight polyethylene glycol conjugated interferon alpha" and
"PEG.sub.12000-IFN alpha" as used herein mean conjugates such as
are prepared according to the methods of International Application
No. WO 95/13090 and containing urethane linkages between the
interferon alpha-2a or -2b amino groups and polyethylene glycol
having an average molecular weight of 12000.
[0015] The preferred PEG.sub.12000-interferon alpha-2b is prepared
by attaching a PEG polymer to the epsilon amino group of a lysine
residue in the IFN alpha-2b molecule. A single PEG.sub.12000
molecule is conjugated to free amino groups on an IFN alpha-2b
molecule via a urethane linkage. This conjugate is characterized by
the molecular weight of PEG.sub.12000 attached. The
PEG.sub.12000-IFN alpha-2b conjugate is formulated as a lyophilized
powder for injection. The objective of conjugation of IFN alpha
with PEG is to improve the delivery of the protein by significantly
prolonging its plasma half-life, and thereby provide protracted
activity of IFN alpha.
[0016] The term "interferon-alpha" as used herein means the family
of highly homologous species-specific proteins that inhibit viral
replication and cellular proliferation and modulate immune
response. Typical suitable interferon-alphas include, but are not
limited to, recombinant interferon alpha-2b such as Intron-A
interferon available from Schering Corporation, Kenilworth, N.J.,
recombinant interferon alpha-2a such as Roferon interferon
available from Hoffmann-La Roche, Nutley, N.J., recombinant
interferon alpha-2C such as Berofor alpha 2 interferon available
from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn.,
interferon alpha-n1, a purified blend of natural alpha interferons
such as Sumiferon available from Sumitomo, Japan or as Wellferon
interferon alpha-n1 (INS) available from the Glaxo-Wellcome Ltd.,
London, Great Britain, or a consensus alpha interferon such as
those described in U.S. Pat. Nos. 4,897,471 and 4,695,623
(especially Examples 7, 8 or 9 thereof) and the specific product
available from Amgen, Inc., Newbury Park, Calif., or interferon
alpha-n3 a mixture of natural alpha interferons made by Interferon
Sciences and available from the Purdue Frederick Co., Norwalk,
Conn., under the Alferon Tradename. The use of interferon alpha-2a
or alpha-2b is preferred. Since interferon alpha-2b, among all
interferons, has the broadest approval throughout the world for
treating chronic hepatitis C infection, it is most preferred. The
manufacture of interferon alpha-2b is described in U.S. Pat. No.
4,530,901.
[0017] Other interferon alpha conjugates can be prepared by
coupling an interferon alpha to a water-soluble polymer. A
non-limiting list of such polymers include other polyalkylene oxide
homopolymers such as polypropylene glycols, polyoxyethylenated
polyols, copolymers thereof and block copolymers thereof. As an
alternative to polyalkylene oxide-based polymers, effectively
non-antigenic materials such as dextran, polyvinylpyrrolidones,
polyacrylamides, polyvinyl alcohols, carbohydrate-based polymers
and the like can be used. Such interferon alpha-polymer conjugates
are described in U.S. Pat. No. 4,766,106, U.S. Pat. No. 4,917,888,
European Patent Application No. 0 236 987, European Patent
Application Nos. 0 510 356, 0 593 868 and 0 809 996 (pegylated
interferon alpha-2a) and International Publication No. WO
95/13090.
[0018] Pharmaceutical composition of pegylated interferon
alpha-suitable for parenteral administration may be formulated with
a suitable buffer, e.g., Tris-HCl, acetate or phosphate such as
dibasic sodium phosphate/monobasic sodium phosphate buffer, and
pharmaceutically acceptable excipients (e.g., sucrose), carriers
(e.g. human serum albumin), toxicity agents (e.g. NaCl),
preservatives (e.g. thimerosol, cresol or benylalcohol), and
surfactants (e.g. tween or polysorabates) in sterile water for
injection. The pegylated interferon alpha-may be stored as
lyophilized powders under a refrigeration at 2.degree.-8.degree. C.
The reconstituted aqueous solutions are stable when stored between
2.degree. and 8.degree. C. and used within 24 hours of
reconstitution. See for example U.S. Pat. Nos., 4,492,537;
5,762,923 and 5,766,582. The reconstituted aqueous solutions may
also be stored in prefilled, multi-dose syringes such as those
useful for delivery of drugs such as insulin. Typical suitable
syringes include systems comprising a prefilled vial attached to a
pen-type syringe such as the NOVOLET Novo Pen available from Novo
Nordisk, as well as prefilled, pen-type syringes which allow easy
self-injection by the user. Other syringe systems include a
pen-type syringe comprising a glass cartridge containing a diluent
and lyophilized pegylated interferon alpha powder in a separate
compartment.
[0019] The term "patients having melanoma" as used herein means any
patient having melanoma and includes treatment-naive patients as
well as treatment-experienced patients as well as patients in the
Stage IIB or Stage III cutaneous melanoma. All patients having
melanoma are preferably treated by wide excision of the primary
melanoma lesion prior to initiation of the improved therapy of the
present invention.
[0020] The term "treatment-naive patients" as used herein means
patients with melanoma including newly-diagnosed melanoma patients
who have never been treated with any chemotherapeutic drugs, e.g.
dacarbazine ("DTIC") or immunotherapy, e.g., IL-2 as well as any
interferon, including but not limited to interferon alpha, or
pegylated interferon alpha. All treatment-naive patients having
melanoma are preferably treated by wide excision of the primary
melanoma lesion prior to initiation of the improved therapy of the
present invention.
[0021] The term "treatment-experienced patients" as used herein
means those patients who have initiated some form of
chemotherapeutic drug, e.g., DTIC or immunotherapy including, but
not limited to interferon-alpha, IL-2 and GMCSF. All
treatment-experienced patients having melanoma are preferably
treated by wide excision of the primary melanoma lesion prior to
initiation of the improved therapy of the present invention.
[0022] The term "primary cutaneous melanoma" as used herein means
histologically proven primary cutaneous melanoma as defined by the
current (1992) American Joint Committee on Cancer Staging Criteria
("AJCC"): in the AJCC Manual for Strategy of Cancer (4th edition)
Philadelphia, Pa. Lippincott Publishers 1992 and includes (a) node
negative stage IIB disease with deep primary melanomas of Breslow
depth more than 4 mm and (b)node positive stage III disease
defined, as follows: (1) deep primary melanomas of Breslow depth
more than 4 mm (designated CS1 PSi: T4N0M0); (2) primary melanomas
of any tumor stage in the presence of N1 regional lymph node
metastasis detected at elective lymph node dissection with
clinically inapparent regional lymph node metastasis (designated
CS1 PS2: any TpN1 M0); (3) clinically apparent N1 regional lymph
node involvement synchronous with primary melanoma of T1-4
(designated CS2 PS2: any TcN1M0); and (4) regional lymph node
recurrence at any interval after appropriate surgery for primary
melanoma of any depth (designated CS2R: TxrN1 M0 recurrent).
Patients in groups 1 to 3 were required to enter this study within
56 days of first primary melanoma biopsy. Patients with regional
nodal relapse in group 4 were required to enter this study within
42 days of lymphadenectomy.
[0023] All patients with stage III melanoma should be treated by
wide excision of the primary melanoma lesion.
[0024] Patients with clinically positive nodes in the groin, axilla
or neck should have a full lymphadenectomy to surgically remove
these cites.
[0025] All surgery should be completed within 56 days prior to
randomization into this clinical study.
[0026] The term "progression-free survival time" ("PFST") as used
herein means the time from initiation of melanoma treatment in
accordance with the present invention to the documentation of
disease progression or recurrence by histological or cytological
evidence
[0027] The progression-free survival time expected for melanoma
patients treated in accordance with the method of this invention is
at least about 4 years from initiation of the melanoma therapy of
this invention; preferably the PFST is in the range of about 30 to
about 43 months from initiation of the melanoma therapy of this
invention.
[0028] The increase in the progression-free survival time expected
for melanoma patients treated in accordance with the method of this
invention is greater than about 1.0 years to about 1.5 years
compared to control (observation).
[0029] The following criteria of treatment failure constitute the
only acceptable evidence of disease recurrence or progression:
[0030] Lung/Liver:
[0031] Positive cytology or biopsy in the presence of a single new
lesion or the appearance of multiple lesions consistent with
metastatic disease.
[0032] Central Nervous System:
[0033] A positive brain CT or MRI scan or Cerebrospinal fluid (CSF)
cytology.
[0034] Cutaneous, Subcutaneous and Lymph Node Recurrence:
[0035] Positive cytology or biopsy.
[0036] Bone and Other Organs:
[0037] Positive cytology or biopsy in the presence of a single new
lesion or the appearance of multiple lesions consistent with
metastatic disease identified by two different radiologic studies:
i.e., positive gallium scan and contrast GI series or ultrasound,
x-ray or CT of abdomen for abdominal disease.
[0038] The term "prohibited medications" as used herein includes
the following:
[0039] a) Other chemotherapy, hormonal, immunologic, biologic or
radiation therapy.
[0040] b) Colony stimulating factors including erythropoietin and
G-CSF.
[0041] c) Other investigational drugs.
[0042] d) Chronic systemic corticosteroid therapy.
[0043] Melanoma patients treated in accordance with the method of
the present invention should not receive any of the above-listed
prohibited medications during the treatment period.
[0044] Pegylated interferon-alpha formulations are not effective
when administered orally, so the preferred method of administering
the pegylated interferon-alpha is parenterally, preferably by
subcutaneous, IV, or IM, injection. Of course, other types of
administration of both medicaments, as they become available are
contemplated, such as by nasal spray, transdermally, by
suppository, by sustained release dosage form, and by pulmonary
inhalation. Any form of administration will work so long as the
proper dosages are delivered without destroying the active
ingredient.
[0045] The following Clinical Study Design may be used to treat
melanoma patients in accordance with the method of the present
invention. Many modifications of this Clinical Study Design
protocol will be obvious to the skilled clinician, and the
following Study Design should not be interpreted as limiting the
scope of the method of this invention which is defined by the
claims listed hereinafter.
Clinical Study Design
[0046] This is a Phase II/III randomized, controlled, multicenter,
open-label study designed to assess he safety, efficacy, and impact
on quality of life of PEG Intron (pegylated interferon alpha 2b
i.e. PEG.sub.12000-interferon alpha 2b and INTRON.RTM. A
(interferon alpha 2b), which are each available from Schering
Corporation, Kenilworth, N.J., and the population pharmacokinetics
of PEG Intron when given as adjuvant therapy in subjects with
resected Stage III node-positive cutaneous melanoma. It is
anticipated that approximately 450 subjects will be enrolled, with
225 subjects randomized to each treatment group.
[0047] Subjects will enter the study within 56 days of definitive
surgery for their Stage III melanoma and will be randomized to one
of the two treatment groups shown below. Definitive surgery
includes wide surgical excision of the primary melanoma and
lymphadenectomy of all clinically positive nodes in the groin,
axilla and neck. All surgery should be complete at least 56 days
prior to randomization.
[0048] Group A: INTRON.RTM. A
[0049] 20 MIU/m.sup.2/day IV 5 days/week.times.4 weeks, followed by
10 MIU/m.sup.2 SC TIW.times.48 weeks.
[0050] Induction Therapy: 20 MIU/m.sup.2/day IV 5 days a week for 4
weeks
[0051] All subjects randomized to Treatment Group A, will begin
induction therapy with intravenous INTRON.RTM. A, 20 million
international units/m.sup.2/day, 5 days/week for 4 weeks.
Acetaminophen (500-1000 mg) may be given in the clinic 30 minutes
prior to receiving the first dose of INTRON.RTM. A. Subjects should
be observed for 2 hours after the first dose. Acetaminophen
(500-650 mg PO q 4-6 hours) should be continued as needed, and
should not exceed 3000 mg/day.
[0052] Maintenance Therapy: 10 MIU/m.sup.2 SC TIW for 48 weeks.
[0053] After induction therapy, subjects will continue on
maintenance therapy and receive INTRON.RTM. A, 10 million
international units/m.sup.2/day, SC three times weekly for 48
weeks.
[0054] Group B: PEG Intron: PEG.sub.12000-interferon alpha-2b, 6.0
.mu.g/kg, SC once weekly for 2 years.
[0055] Subjects randomized to treatment Group B will receive
PEG.sub.12000-interferon alpha-2b, 6.0 .mu.g/kg, SC once weekly for
2 years. Acetaminophen (500-1000 mg) may be given in the clinic 30
minutes prior to receiving the first dose of PEG Intron. Subjects
should be observed for 2 hours after the first dose. Acetaminophen
(500-650 mg PO q 4-6 hours) should be continued as needed, and
should not exceed 3000 mg/day.
Duration of Study and Visit Schedule
[0056] Treatment with either PEG.sub.12000-interferon alpha 2b
(about 104 weeks) or INTRON.RTM. A (52 weeks) will continue as
scheduled unless there is evidenced of disease recurrence,
unacceptable toxicity, or the subject requests that therapy be
discontinued. Tolerability of the respective study treatment and
quality of life will be assessed from clinical observation, routine
lab oratory testing, and quality of life assessments over the
course of therapy. Following completion of therapy, subjects will
continue to be followed for evidenced of disease recurrence and
will complete quality of life assessments. If the melanoma recurs,
further treatment will be at the discretion of the physician. All
subjects will be followed for survival, regardless of when they
discontinue therapy. Analyses of relapse-free and overall survival,
regardless of when they discontinue therapy. Analyses of
relapse-free and overall survival will be event driven.
[0057] The duration of this study is based upon achieving a
therapeutic response, and will be determined for each subject
individually.
[0058] The study population will include male and female patients
with cutaneous melanoma and will be included if they meet the
following inclusion and exclusion criteria:
Subject Inclusion Criteria
[0059] A subject is eligible to participate in this study if he or
she:
[0060] a) Subjects must have histologically documented primary
cutaneous melanoma meeting one of the following staging
Criteria:
[0061] Primary melanoma of any stage in the presence of N1 regional
lymph node metastases detected at elective lymph node dissection or
sentinel node biopsy, with clinically inapparent regional lymph
node metastasis (any pTN.sub.1M.sub.0).
[0062] Clinically apparent N1 or N2a regional lymph node
involvement synchronous with primary melanoma of T.sub.1-4 (any
pTrN.sub.1-2aM.sub.0).
[0063] Regional lymph node recurrence at any interval after
appropriate surgery for primary melanoma of any depth (any
pTrN.sub.1-2aM.sub.0).
[0064] b) Subjects must have had all known disease completely
resected with adequate surgical margins within 56 days prior to
randomization into the study.
[0065] c) Subjects must have an ECOG performance status of 0 or 1
as defined by Minna, J D, et al. "Cancer of the Lung" in DeVita V,
et al. eds., Cancer: Principles and Practiced of Oncology,
Lippincott, Philadelphia, Pa. 1989 at page 536.
[0066] d) Subjects must be between 18-70 years old.
[0067] e) Subjects must have adequate hepatic, renal and bone
marrow function as defined by the following parameters obtained
within 14 days prior to initiation of study treatment.
[0068] 1) Hematology:
[0069] White Blood count (WBC) .gtoreq.3,000 cells/.mu.L.
[0070] Hemoglobin concentration .gtoreq.9 g/dL.
[0071] 2) Renal and hepatic function:
[0072] Serum creatinine .ltoreq.2.0 mg/dL or calculated creatinine
clearance of .gtoreq.50 mL/minute.
[0073] Serum bilirubin <2 times the upper limit of normal (ULN),
unless due to infiltration by disease.
[0074] AST/ALT (SGOT/SGPT) <2 times ULN.
[0075] f) has submitted a written voluntary informed consent before
study entry, is willing to participate in this study and will
complete all follow up assessments.
Subject Exclusion Criteria
[0076] A subject is not eligible to participate in this study if he
or she:
[0077] a) Subjects who have received any prior chemotherapy,
immunotherapy hormonal or radiation therapy for melanoma.
[0078] b) Subjects who have evidence of distant or non-regional
lymph node metastases, in-transit metastases, or positive lymph
nodes with an unknown primary.
[0079] c) Subjects whose disease cannot be completely surgically
resected because of gross extracapsular extension.
[0080] d) Subjects who have previously received interferon-.alpha.
for any reason. (Such patients however, are still considered
treatable in accordance with the method of this invention but are
only excluded from this registration study.)
[0081] e) Subjects who have severe cardiovascular disease, i.e.,
arrhythmias requiring chronic treatment, congestive heart failure
(NYHA Class III or IV) or symptomatic ischemic heart disease as
defined by Bruce RA: Evaluation of Functional Capacity and Exercise
Tolerance of Cardiac Subjects" in Mod. Concepts Cardiovasc Dis
1956; 25-321.
[0082] f) Subjects who have a history of neuropsychiatric disorder
requiring hospitalization.
[0083] g) Subjects with thyroid dysfunction not responsive to
therapy.
[0084] h) Subjects with uncontrolled diabetes mellitus.
[0085] I) Subjects with a history of prior malignancy within the
past 5 years other than surgically cured non-melanoma skin cancer
or cervical carcinoma in situ.
[0086] j) Subjects who have a history of seropositivity for
HIV.
[0087] k) Subjects who are pregnant, lactating, or of reproductive
potential and not practicing an effective means of
contraception.
[0088] l) Subjects with active and/or uncontrolled infection,
including active hepatitis.
[0089] m) Subjects with a medical condition requiring chronic
systemic corticosteroids.
[0090] n) Subjects who are known to be actively abusing alcohol or
drugs.
[0091] o) Subjects who have received any experimental therapy
within 30 days prior to randomization in this study.
[0092] p) Subjects who have not recovered from the effects of
recent surgery.
Subject Discontinuation Criteria
[0093] It is the right and duty of the clinical investigator to
interrupt the treatment of any subject whose health or well being
may be threatened by continuation in this study.
[0094] Subjects may be discontinued prior to completion of this
study for any of the following reasons:
[0095] a) Develops documented progression or recurrence of disease,
as defined herein above.
[0096] b) Has a clinically significant adverse event as determined
by the Principal Investigator.
[0097] c) Requests to be withdrawn from the study.
[0098] d) Is unable to complete the study evaluations/visits
because of unforeseen circumstances.
[0099] e) Develops other conditions for which, in the
investigator's opinion warrants withdrawal from the study
[0100] f) Develops severe depression or any other psychiatric
disorder requiring hospitalization.
[0101] g) Experiences a serious allergic response to the study drug
manifested by angioedema, bronchoconstriction or anaphylaxis.
[0102] h) Receives treatment with a prohibited medication as
indicated herein above.
[0103] I) Experiences recurrent toxicities despite dose
modifications as described herein below.
[0104] All subjects will be followed for survival, regardless of
when they go off study. Subjects who discontinue for reasons other
than recurrence of disease should also be followed for recurrence
and survival.
Analysis of Primary and Secondary Endpoints
[0105] The primary endpoint will be progression-free survival (PFS)
time, defined to be the time from randomization to progression or
death. PFS will be assessed by clinical observation, with
recurrence documented by appropriate radiographic and histologic
methods, and confirmed by Independent Central Review.
[0106] The secondary endpoints will be overall survival, safety,
quality of life, and population pharmacokinetics (PK). Safety and
tolerability will be assessed from clinical observation and routine
laboratory testing over the course of therapy. Health-Related
Quality of Life (HQL) will be assessed from an HQL
questionnaire.
[0107] Population pharmacokinetics will be assessed from periodic
serum sampling in the PEG Intron group.
[0108] Subjects enrolled in Group A who are not able to tolerate
the IV induction dose regimen despite dose modification, should
stop the IV regimen but should not be discontinued from the study.
After resolution of toxicity, they may enter the INTRON.RTM. A
maintenance phase with the full maintenance dose.
* * * * *